Neuronal growth and differentiation is important in a wide variety of processes from neuronal development to memory. The ability to modulate such growth and differentiation is important for the study of neurons as well as for the treatment of diseases and conditions that involve neuronal growth, degradation, or injury. For example, many neurodegenerative diseases, such as Alzheimer's Disease and Huntington's Disease, are characterized by the death of neurons. Traumatic injuries to nerves, including trauma to the spine and damage caused by ischemic cerebral stroke, can involve neuronal death. Any of these conditions can potentially be treated using agents that promote growth of neurons. Additionally, the generation of long-term memory is believed to result from strengthening of neuronal connections and synaptic remodeling.
Fucoseα(1-2) galactose (abbreviated herein as Fucα(1-2)Gal), which exists as a terminal carbohydrate modification to N- and O-linked glycoproteins, has been implicated in modulating neuronal processes such as learning and memory. For instance, preventing formation of Fuceα(1-2)Gal linkages by incorporation of 2-deoxy-D-galactose (2-dGal) into glycan chains has been shown to cause reversible amnesia in animals. (Bullock, S. et al., J. Neurochem., 54:135-142 (1990); Rose, S. P. R., et al., Behav. Neural Biol., 48:246-258 (1987); Lorenzini, C. G. A. et al., Neurobiol. Learn. Mem., 68:317-324 (1997)). 2-dGal also interferes with the maintenance of long-term potentiation (LTP), a form of synaptic plasticity that is closely associated with learning and memory. (Krug, M., et al., Brain Res., 540:237-242 (1991)). Moreover, injection of a monoclonal antibody specific for Fucα(1-2)Gal has been found to impair memory formation in animals, presumably by blocking the Fucα(1-2)Gal epitope (Karsten, U., et al., Br. J. Cancer 58:176-181 (1988); Jork, R., et al., Neurosci. Res. Comm. 8:21-27 (1991)).
The fucosylation of neuronal proteins may be regulated in response to synaptic activity. Both task-specific learning and LTP have been shown to induce the fucosylation of proteins at the synapse (McCabe, N. R., et al., Neurochem. Res., 10:1083-1095 (1985); Pohle. W., et al., Brain Res., 410:245-256 (1987)). Notably, addition of exogenous fucose or 2′fucosyllactose was found to enhance LTP in hippocampal slices (Matthies, H., et al., Brain Res., 725:276-280 (1996)). Furthermore, the activity of fucosyltransferases, enzymes involved in the transfer of fucose into glycoproteins, has been demonstrated to increase substantially during synaptogenesis (Matsui, Y., et al., J. Neurochem., 46:144-150 (1986)) and upon passive avoidance training in animals (Popov, N., et al., Pharmacol. Biochem. Behav., 19:43-47 (1983)). These results suggest that the fucosylation of certain neuronal proteins may be highly regulated in the brain and contribute to synaptic plasticity. Despite these intriguing observations, little is known about the molecular mechanisms by which Fucα(1-2)Gal sugars influence neuronal communication processes. Surprisingly, no Fucα(1-2)Gal glycoproteins have been characterized from the brain, and the precise roles of the sugars in regulating the structure and function of neuronal proteins is presently unclear.
A need exists for a product and process for modulating neuronal processes such as learning and memory. Furthermore, a need exists for a product and a process for modulating neuronal cell growth, which is, among other functions, involved in modulating learning and memory and recovery from neuronal disorders or damage. An additional need exists for a compound and method to improve growth of neural stem cells.